Purpose :
The adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that plays a crucial role in maintaining energy homeostasis. AMPK is a biosensor that can detect minute fluctuations in AMP/ATP ratios, and becomes activated when endogenous AMP is high and ATP is low within the cell. Active AMPK can then inhibit the downstream mammalian target of rapamycin (mTOR), a key regulator of cell growth and protein synthesis. Here, we asked whether there is metabolic stress in experimental glaucoma and, if so, does it result in AMPK activation, loss of mTOR function and neurodegeneration?

Methods :
Unilateral elevation of intraocular pressure was induced in C57BL/6 mice by injection of magnetic microbeads into the anterior chamber. AMPK or mTOR activity was assessed by immunohistochemistry with antibodies against phospho-AMPK or phospho-S6 respectively, in combination with RGC-specific markers. In vivo inhibition of AMPK was achieved by administration of compound C or by intravitreal injection of siRNA to selectively knockdown AMPK expression. mTORC1 function was inhibited with rapamycin. RGC soma or axons were quantified on Brn3a-labeled retinas or toluidine blue-stained optic nerve sections, respectively. RGC dendrites were analyzed in Thy1-YFP mice subjected to ocular hypertension followed by 3D reconstruction of dendritic arbors.

Conclusions :
This study reveals that ocular hypertension leads to early metabolic stress in glaucoma which contributes to RGC damage through activation of the energy biosensor AMPK and loss of mTOR signaling in vulnerable neurons

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.